RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
基于转录组学分析镉诱导的食管鳞状细胞癌进展中的关键基因、潜在机制及治疗药物
英文原题：Transcriptomics-based analysis of key genes and potential mechanism and therapeutic agents in cadmium-induced esophageal squamous cell carcinoma progression.
查看英文原题
Transcriptomics-based analysis of key genes and potential mechanism and therapeutic agents in cadmium-induced esophageal squamous cell carcinoma progression.
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中文摘要
慢性镉暴露与食管鳞状细胞癌（ESCC）的进展、治疗耐药和不良预后相关，但其分子机制仍不清楚。基于对慢性镉处理（CCT）和未处理的人EC109 ESCC细胞的全转录组测序（RNA-seq），我们进行了lncRNA-mRNA共表达和蛋白质-蛋白质相互作用（PPI）网络分析，以筛选与镉暴露相关的枢纽基因。随后，基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析表明，这些基因主要富集于核质运输、铁死亡、亨廷顿病和细胞衰老。基于lncRNA-miRNA-mRNA潜在相互作用，选择三个lncRNA（AC107068.1、TTN-AS1、MAPKAPK5-AS1）和十个mRNA（IPO5、NUDCD1、OSTM1、CCNB1、FANCD2、TFRC、POLR2B、HTT、NUP43、NBN）用于构建竞争性内源RNA（ceRNA）网络。对靶mRNA的连通性图谱（CMap）分析显示，JAK3-inhibitor-I是治疗镉诱导ESCC进展最有前景的药物。随后在TCGA队列、镉处理的癌细胞和41例ESCC标本中验证了候选mRNA的预后价值和异常表达。
此外，进行了迁移和侵袭实验以评估所鉴定基因对细胞恶性表型的影响。结果，IPO5被确定为关键基因，MAPKAPK5-AS1-hsa-miR-379-5p-IPO5被认为是ESCC中镉致癌的潜在ceRNA调控机制。使用TIMER和EPIC算法，IPO5与ESCC组织中CD4+ T细胞和巨噬细胞浸润增加相关，而与CD8+ T细胞和NK细胞呈负相关。
总体而言，我们的研究为理解镉诱导的ESCC进展和治疗耐药所涉及的分子机制提供了宝贵信息。此外，我们预测了用于镉致癌性预防和治疗的潜在药物。
展开英文摘要原文
Chronic cadmium exposure is linked to esophageal squamous cell carcinoma (ESCC) progression, treatment resistance, and poor prognosis, but its molecular mechanisms remain unclear. Based on whole-transcriptome sequencing (RNA-seq) on chronic cadmium-treated (CCT) and untreated human EC109 ESCC cells, we performed lncRNA-mRNA co-expression and protein-protein interaction (PPI) network analyses to screen the hub genes related to cadmium exposure. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses depicted that these genes were mainly enriched in nucleocytoplasmic transport, ferroptosis, Huntington disease, and cellular senescence.
Based on the lncRNA-miRNA-mRNA potential interaction, three lncRNAs (AC107068. 1, TTN-AS1, MAPKAPK5-AS1) and ten mRNAs (IPO5, NUDCD1, OSTM1, CCNB1, FANCD2, TFRC, POLR2B, HTT, NUP43, NBN) were selected for competitive endogenous RNA (ceRNA) network construction.
Connectivity map (CMap) analysis for the target mRNAs showed that JAK3-inhibitor-I was the most promising therapeutic drug for cadmium-induced ESCC progression. The prognostic value and abnormal expression of the candidate mRNAs were then validated in TCGA cohorts, cadmium-treated cancer cells and 41 ESCC specimens.
Moreover, migration and invasion assays were performed to assess the effects of the identified gene on cell malignant phenotypes. As a result, IPO5 was identified as the pivotal gene and MAPKAPK5-AS1-hsa-miR-379-5p-IPO5 was deemed as a potential ceRNA regulatory mechanism for cadmium carcinogenesis in ESCC.
Using TIMER and EPIC algorithms, IPO5 was correlated with increased infiltration of CD4+ T cells and macrophages, while negatively associated with CD8+ T cells and NK cells in ESCC tissues. Collectively, our study provides valuable information in understanding the molecular mechanisms involved in cadmium-induced ESCC progression and treatment resistance.
Furthermore, we predict potential agents for cadmium carcinogenicity prevention and treatment.
论文信息
- 作者
- Zhu R、Chen J、Zhang X、Chen Q、Jin Y、Zeng M、Luo J、Huang Y
- 第一作者单位
- Central Laboratory, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, Guangdong, China.China
- 通讯作者单位
- Central Laboratory, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, Guangdong, China. g_lpeng@stu.edu.cn.China
- 期刊
- Scientific reports2025 Dec 25
- 原文标识
- PubMed 41449178 · DOI 10.1038/s41598-025-32732-1
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